Submissions for variant NM_024675.4(PALB2):c.48+1G>A

dbSNP: rs515726118

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561202	SCV000666892	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-08-30	criteria provided, single submitter	clinical testing	The c.48+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 1 of the PALB2 gene. This alteration has been reported in multiple breast cancer cases (Hellebrand H et al. Hum Mutat, 2011 Jun;32:E2176-88; Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration has also been reported as likely pathogenic in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition. (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635645	SCV000757066	likely pathogenic	Familial cancer of breast	2017-12-18	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). This variant has not been reported in the literature in individuals with PALB2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 1 of the PALB2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
GeneKor MSA	RCV000708619	SCV000821760	likely pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change occurs 1 nucleotides after exon 1 of the PALB2 gene. This position is highly conserved in the human and other genomes and is crucial in mRNA processing. This variant is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Truncating variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). Also, donor and acceptor splice site variants as usual lead to a loss of protein function (PMID: 16199547). This variant has been described in the international literature in an individual undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID:482019).
Color Diagnostics, LLC DBA Color Health	RCV000561202	SCV000913014	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-10-10	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 1 of the PALB2 gene. A minigene splicing assay has shown that this variant results predominantly in the out-of-frame deletion of 17 nucleotides from exon 1 (PMID: 34846068). This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_011230) and in an individual with personal or family history of breast and/or ovarian cancer (PMID: 31159747). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV000635645	SCV004188441	likely pathogenic	Familial cancer of breast	2023-09-05	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.